Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer.
Bioorg Chem
; 131: 106274, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36434952
ABSTRACT
Disruption of protein-protein interaction between transcriptional enhancer factor (TEA)-domain (TEAD; a transcription factor) and its co-activator Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is a potential therapeutic strategy against various types of solid tumors. Based on hit compound 8 and 9a, hydrazone derivatives with dioxo-benzo[d]isothiazole (9b-n) and oxime ester (10a-s) or amide derivatives (11a-r) with dioxo-benzo[b]thiophene were designed and synthesized as novel TEAD-YAP interaction inhibitors. Amide derivative 11q exhibited a higher potency in inhibiting TEAD-YAP reporter expression activity (IC50 = 12.7 µM), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI50 = 3.2 µM), and anchorage-independent growth in soft agar. Molecular docking analysis suggested that the newly synthesized compounds bound to interface 2 of TEAD had lower docking scores compared to the compounds that bind to interface 3; moreover, they were predicted to overlap with YAP. Therefore, we identified 11q as an attractive therapeutic agent for treating solid tumors overexpressing YAP/TAZ.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Coréia do Sul